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The COVID-19 pandemic has led to a significant increase in demand for mental health services for young people. This demand comes on top of a preexisting surge in mental health presentations for our youth, and it places extraordinary demand on support services and the professionals who deliver them. Concurrently, it is recognised that engaging and working with young people and their mental health has its own unique challenges, and that many young people find direct ‘talk-based’ therapies confronting. This article examines the use of a model of group work practice combining the benefits of rhythmic music with reflective discussions as a response to the dual challenges of workplace burnout and client engagement. It reflects on the important role music has to play in young lives and how this can be extended into therapy in a fun and uplifting manner. It draws attention to the long history of rhythmic music within traditional healing practices and the emerging scientific evidence supporting this approach.

American alligators (Alligator mississippiensis) inhabit freshwater wetlands that are vulnerable to salinization caused by anthropogenic alterations to freshwater flow, in addition to storm surges, sea level rise, and droughts. Salinization of coastal freshwater habitats is a growing concern in a changing climate due to increased frequency and intensity of storm surges and drought conditions. This study opportunistically sampled juvenile male and female wild alligators in various salinities each month excluding November, December, and January for one year at Rockefeller Wildlife Refuge in coastal Louisiana. Blood plasma biochemistry parameters including electrolyte levels were subsequently measured. In addition, levels of various renin–angiotensin–aldosterone system hormones, glucocorticoids, androgens, estrogens, and progestogens were analyzed using liquid chromatography and tandem mass spectrometry. Only males were sampled in hyperosmotic environments (> 10‰) during dry conditions in late summer 2018. In juvenile males, plasma Na+, Cl−, and the progestogen 17α,20β-dihydroxypregnenone were significantly and positively correlated with environmental salinity. However, variation in glucocorticoids, androgens, and estrogens were not associated with hypersaline water while sex steroids showed significant seasonal variation. This study demonstrated significant correlation of environmental salinity with electrolyte levels and a sex steroid in wild juvenile alligators, and to our knowledge represents the first measurement of 17α,20β-dihydroxypregnenone in alligators.

Considering that emerging infectious diseases are one of the major drivers of global amphibian decline, controlling the spread of infections are evenmore challenging. Amphibian skin disease chytridiomycosis, which is caused by two species of fungi belonging to the Batrachochytrium genus, has been detected in at least 700 amphibian species causingmass mortalities in all continents where amphibian soccur. Most Alytes species, including the Beticmid wife toad (A. dickhilleni), are highly susceptible to B. dendrobatidis(Bd) with lethal consequences. The presence of Bd infection in A. dickhilleni was confirmed ten years ago in just three localities across the entire distribution range of this threatened species. Here we report the extraordinary Bd expansion through the entire distribution range of A. dickhilleniand analyse if former infected populations acted as the source of transmission events to current infected populations. Currently,Bd infection is broadly distributed across the entire distribution range of the species and the increase of infection prevalence reached 30–50% during a decade. The populations where the infection was detected a decade ago could be identified as likely sources of infection for somelocations where the pathogen is now present. The introduction of infected amphibian hosts into previously naïve A. dickhilleni breeding sites, and otheranthropogenic processes, are seeming to be the most plausible way of Bd range expansion, motivating mass mortalities, population declines and extirpation events of this threatened amphibian species., This work was funded by the Consejería de Medio Ambiente of Junta de Andalucía (Contract Number NET378406/1).

Central to spatial analysis of crime is the assumption that the offender has visited the locations analyzed. We show that even if this is incorrect, meaningful patterns can be identified. Using 390...

The H1 linker histone family is the most abundant group of eukaryotic chromatin-binding proteins. However, their contribution to chromosome structure and function remains incompletely understood. Here we use single-molecule fluorescence and force microscopy to directly visualize the behavior of H1 on various nucleic acid and nucleosome substrates. We observe that H1 coalesces around single-stranded DNA generated from tension-induced DNA duplex melting. Using a droplet fusion assay controlled by optical tweezers, we find that single-stranded nucleic acids mediate the formation of gel-like H1 droplets, whereas H1-double-stranded DNA and H1-nucleosome droplets are more liquid-like. Molecular dynamics simulations reveal that multivalent and transient engagement of H1 with unpaired DNA strands drives their enhanced phase separation. Using eGFP-tagged H1, we demonstrate that inducing single-stranded DNA accumulation in cells causes an increase in H1 puncta that are able to fuse. We further show that H1 and Replication Protein A occupy separate nuclear regions, but that H1 colocalizes with the replication factor Proliferating Cell Nuclear Antigen, particularly after DNA damage. Overall, our results provide a refined perspective on the diverse roles of H1 in genome organization and maintenance, and indicate its involvement at stalled replication forks.

BackgroundOlder age is the main risk factor for chronic lung diseases including idiopathic pulmonary fibrosis (IPF). Halting or reversing progression of IPF remains an unmet clinical need due to limited knowledge of underlying mechanisms. The lung circulatory system, composed of blood (pulmonary and bronchial) and lymphatic vessels networks, has been implicated in IPF pathophysiology in elderly people, based solely on reports of altered density and increased permeability of vessels.AimWe aimed to define heterogeneity and IPF-associated changes of lung endothelial cells (EC or endothelium) by comparing gene expression in tissues from elderly people - transplant donors and recipients with IPF.MethodsSingle-cell RNA sequencing (scRNAseq) datasets of “ageing lung” tissues were selected only from those publicly available sources that contain age-matching samples for both groups (49- 77 years old donors and IPF patients; nine pairs in total), integrated and compared. Findings were validated by immunohistochemistry using EC-specific markers.ResultsThe generation of integrated single-cell maps of ageing lung tissues revealed 17 subpopulations of endothelium (12 for blood and 5 for lymphatic vessels, including 9 novel), with distinct transcriptional profiles. In IPF lung, the heterogeneity of ageing lung endothelium was significantly altered - both in terms of cell numbers (linked to disease- related changes in tissue composition) and differentially expressed genes (associated with fibrosis, inflammation, differentiation and vasodilation) in individual pulmonary, bronchial and lymphatic EC subpopulations.ConclusionsThese findings reveal underappreciated extent of heterogeneity and IPF-associated changes of ageing lung endothelium. Our data suggest direct involvement of specific subpopulations of ageing lung endothelium in IPF pathophysiology, uncovering cellular and molecular targets which may have potential diagnostic, prognostic and therapeutic relevance. This study creates a conceptual framework for appreciating the disease-specific heterogeneity of ageing lung endothelium as a hallmark of IPF.

The American ‘opioid crisis’ is rapidly spreading internationally. Perioperative opioid use increases the risk of long-term opioid use. We review opioid use following wrist and ankle fracture fixation across Scotland, establishing prescribing patterns and associations with patient, injury, or perioperative factors. Six Scottish orthopedic units contributed. A total of 598 patients were included. Patient demographics were similar across all sites. There was variation in anesthetic practice, length of stay, and AO fracture type (p < 0.01). For wrist fractures, 85.6% of patients received a discharge opioid prescription; 5.0% contained a strong opioid. There was no significant variation across the six units in prescribing practice. For ankle fractures, 82.7% of patients received a discharge opioid prescription; 17% contained a strong opioid. Dundee and Edinburgh used more strong opioids; Inverness and Paisley gave the least opioids overall (p < 0.01). Younger patient age, location, and length of stay were independent predictors of increased prescription on binary regression. Despite variability in perioperative practices, discharge opioid analgesic prescription remains overwhelmingly consistent. We believe that the biggest influence lies with the prescriber-institutional ‘standard practice’. Education of these prescribing clinicians regarding the risk profile of opioids is key to reducing their use following surgery, thus lowering long-term opioid dependence.

Between September 1944 and March 1945, more than a thousand V-2 rockets struck Great Britain, causing 2,754 deaths. M.I.5 responded with an ingenious scheme to mislead the Germans so they would sho...

The use of aqueous film forming foams (AFFFs) as fire retardants is an critical point-source for per- and polyfluoroalkyl substances (PFASs) pollution into the aquatic environment. This study investigated PFASs pollution in the surface waters and biota (shellfish and fish) of Galveston Bay, following AFFFs use to extinguish a petrochemical fire (March 17th to 20th, 2019) of oil storage tanks at the International Terminals Company (ITC) in Deer Park (Houston, TX). The levels of up to twelve EPA priority PFASs were measured in surface waters and biota from March–November 2019. PFASs levels in surface waters showed mean total levels in March and April 2019 to be from 4× to ~300× higher than those measured in the following months. PFOS (perfluorooctanesulfonic acid) was the most abundant homolog measured at ≥66% of total PFASs. Maximal PFOS levels exceeded the State of Texas' water regulatory limit of 0.6 μg L−1 in 3% of the samples analyzed in March and April 2019. PFOS was also the most prominent homolog (≥66% of total PFASs) measured in eastern oysters (Crassostrea virginica), red drum (Sciaenops ocellatus), gafftopsail catfish (Bagre marinus), and spotted seatrout (Cynoscion nebulosus). A statistically significant elevation of PFOS body-burdens was measured in oysters and spotted seatrout in April and May 2019, respectively. A Hazard Ratio calculation for seafood safety suggests an advisory of 1–2 meals per week for gafftopsail catfish and red drum, and 2 meals per week for spotted seatrout to be protective for human exposure to PFOS. The levels in oysters indicated no immediate concerns for the dietary exposure of humans. Our results highlight a need for continual monitoring to assess the long-term fate and seafood advisories for PFASs.

CPI-613 is a mitochondrial metabolism disrupter that inhibits tricarboxylic acid (TCA) cycle activity. The consequences of TCA cycle disruption on various metabolic pathways and overall organismal physiology are not fully known. The present study integrates in vivo experimental data with an in silico stoichiometric metabolism model of zebrafish to study the metabolic pathways perturbed under CPI-613 exposure. Embryo-larval life stages of zebrafish (Danio rerio) were exposed to 1 μM CPI-613 for 20 days. Whole-organism respirometry measurements showed an initial suppression of O2 consumption at Day 5 of exposure, followed by recovery comparable to the solvent control (0.01% DMSO) by Day 20. Comparison of whole-transcriptome RNA-sequencing at Day 5 vs. 20 of exposure showed functional categories related to O2 binding and transport, antioxidant activity, FAD binding, and hemoglobin complexes, to be commonly represented. Metabolic enzyme gene expression changes and O2 consumption rate was used to parametrize two in silico stoichiometric metabolic models representative of Day 5 or 20 of exposure. Computational simulations predicted impaired ATP synthesis, α-ketoglutarate dehydrogenase (KGDH) activity, and fatty acid β-oxidation at Day 5 vs. 20 of exposure. These results show that the targeted disruption of KGDH may also impact oxidative phosphorylation (ATP synthesis) and fatty acid metabolism (β-oxidation), in turn influencing cellular bioenergetics and the observed reduction in whole-organism O2 consumption rate. The results of this study provide an integrated in vivo and in silico framework to study the impacts of metabolic disruption on organismal physiology.

Geographic profiling, a mathematical model originally developed in criminology, is increasingly being used in ecology and epidemiology. Geographic profiling boasts a wide range of applications, such as finding source populations of invasive species or breeding sites of vectors of infectious disease. The model provides a cost-effective approach for prioritizing search strategies for source locations and does so via simple data in the form of the positions of each observation, such as individual sightings of invasive species or cases of a disease. In doing so, however, classic geographic profiling approaches fail to make the distinction between those areas containing observed absences and those areas where no data were recorded. Absence data are generated via spatial sampling protocols but are often discarded during the inference process. Here we construct a geographic profiling model that resolves these issues by making inferences via count data, analyzing a set of discrete sentinel locations at which the number of encounters has been recorded. Crucially, in our model this number can be zero. We verify the ability of this new model to estimate source locations and other parameters of practical interest via a Bayesian power analysis. We also measure model performance via real-world data in which the model infers breeding locations of mosquitoes in bromeliads in Miami-Dade County, Florida, USA. In both cases, our novel model produces more efficient search strategies by shifting focus from those areas containing observed absences to those with no data, an improvement over existing models that treat these areas equally. Our model makes important improvements upon classic geographic profiling methods, which will significantly enhance real-world efforts to develop conservation management plans and targeted interventions.

Hurricane Harvey (category four storm) made landfall along the coast of Texas (United States) and then stalled out over Texas and Louisiana, releasing 1.29 × 1011 m3 of precipitation over 5 days. This caused extensive flooding that elevated freshwater river discharge and land runoff into Galveston Bay and eventually into the Gulf of Mexico. The floodwaters delivered a significant influx of dissolved organic carbon (DOC), organic pollutants and nutrients along with terrestrial and freshwater associated microbes. Over the 24 days following the flooding event, samples were collected on five cruises across Galveston Bay from the mouth of the San Jacinto River (Houston, TX, United States) to the Gulf of Mexico. Parameters measured for this study include: water quality (temperature, salinity, pH, and dissolved oxygen), nutrients (NO3–, NO2–, NH4+, Pi, and HSiO3–), polycyclic aromatic hydrocarbons (PAHs), pharmaceuticals (cotinine, carbamazepine, carbamazepine-epoxide, and prednisone), biocide (imidacloprid), DOC, bacteria, and the eukaryotic community composition (16S and 18S rRNA genes). In the week after the flood event, bay-wide salinities decreased to 0–5 compared to the higher pre-Harvey salinities of 20–30 (recorded 5 days before the flood). Water treatment facilities and petrochemical plants were compromised due to the heavy flooding in the region. Increased concentrations of DOC, nutrients, PAHs, pharmaceuticals, and biocides were observed across Galveston Bay immediately following the storm. During the 4 weeks after Harvey, concentrations of DOC, nutrients, and organic pollutants began to decrease coinciding with rising salinities as the freshwater was flushed into the Gulf of Mexico and seawater began moving back into the Bay. Successive blooms of Chlorophyta, diatoms (Bacillariophyta), and dinoflagellates (Dinophyta) occurred similar to post-storm communities from past hurricanes that have impacted estuarine systems along the Gulf of Mexico. The bacterial community showed an increase in the abundance of bacteria associated with terrestrial soils and freshwater at the initial time point and then decreased over time and were replaced by their estuarine and marine relatives within the month following the hurricane. The eukaryotic community changed substantially following Harvey and did not recover to pre-Harvey conditions during our study period, suggesting a longer recovery time compared to the prokaryotes. Although the water quality parameters and prokaryotic community showed signs of returning to pre-Harvey conditions within the month following the flood event, long-term impacts need to be measured in the years following the flood.

Tigers are critically endangered due to deforestation and persecution. Yet in places, Sumatran tigers (Panthera tigris sumatrae) continue to coexist with people, offering insights for managing wildlife elsewhere. Here, we couple spatial models of encounter risk with information on tolerance from 2386 Sumatrans to reveal drivers of human–tiger conflict. Risk of encountering tigers was greater around populated villages that neighboured forest or rivers connecting tiger habitat; geographic profiles refined these predictions to three core areas. People’s tolerance for tigers was related to underlying attitudes, emotions, norms and spiritual beliefs. Combining this information into socio-ecological models yielded predictions of tolerance that were 32 times better than models based on social predictors alone. Pre-emptive intervention based on these socio-ecological predictions could have averted up to 51% of attacks on livestock and people, saving 15 tigers. Our work provides further evidence of the benefits of interdisciplinary research on conservation conflicts., Human-tiger conflict occurs where there is a higher risk of encountering tigers. Here, Struebig et al. use geographic profiling to predict risk of encounters in Sumatra, and show that combining risk measures with social data on tolerance could help prioritise regions for conflict mitigation efforts.

Poaching can have devastating impacts on animal and plant numbers, and in many countries has reached crisis levels, with illegal hunters employing increasingly sophisticated techniques. We used data from an 8-year study in Savé Valley Conservancy, Zimbabwe, to show how geographic profiling-a mathematical technique originally developed in criminology and recently applied to animal foraging and epidemiology-can be adapted for use in investigations of wildlife crime. The data set contained information on over 10,000 incidents of illegal hunting and the deaths of 6,454 wild animals. We used a subset of data for which the illegal hunters' identities were known. Our model identified the illegal hunters' home villages based on the spatial locations of the hunting incidences (e.g., snares). Identification of the villages was improved by manipulating the probability surface inside the conservancy to reflect the fact that although the illegal hunters mostly live outside the conservancy, the majority of hunting occurs inside the conservancy (in criminology terms, commuter crime). These results combined with rigorous simulations showed for the first time how geographic profiling can be combined with GIS data and applied to situations with more complex spatial patterns, for example, where landscape heterogeneity means some parts of the study area are less likely to be used (e.g., aquatic areas for terrestrial animals) or where landscape permeability differs (e.g., forest bats tend not to fly over open areas). More broadly, these results show how geographic profiling can be used to target antipoaching interventions more effectively and more efficiently and to develop management strategies and conservation plans in a range of conservation scenarios.

High usage of the synthetic glucocorticoids (GCs) has led to significant presence of this pharmaceutical group in surface waters where it can affect non-target organisms such as fish. Assessment of a fish's metabolism and swimming performance provide reliable sub-lethal measures of effects of GCs on oxygen-requiring processes and ability to swim. In this study, we determined time-dependent (7, 14 and 21 days) effects of the synthetic GC prednisone (1 μg L−1) on sheepshead minnow (SHM) (Cyprinodon variegatus). Standard (SMR), routine (RMR) and maximum (MMR) metabolic rate, metabolic scope (MS), excess post-exercise oxygen consumption (EPOC), cost of transport (COT) and critical swimming speed (Ucrit) were determined. Twenty-one days exposure to prednisone resulted in significantly higher SMR, RMR, MMR, MS, EPOC and COT compared with 7d and 14d prednisone fish. However, Ucrit was not significantly different between prednisone and solvent control exposed fish (within 7d, 14d, 21d groups). SMR, RMR and MMR were lower in the 7d and 14d prednisone exposed fish compared with their solvent control groups. In contrast, SMR, RMR and MMR were all significantly higher in the 21d prednisone exposed fish compared with solvent control. EPOC was significantly higher in 14d prednisone exposed fish and trending higher in 21d and 7d prednisone exposed fish compared with their solvent controls. EPOC was significantly higher in 21d compared with 7d prednisone exposed fish. A significantly higher COT was seen in the 21d compared with 7d and 14d prednisone fish. Collectively, this study showed time-dependent effects of prednisone on SHM metabolism and swimming performance.

Aim The development of conservation plans, including those dealing with invasive species, is underpinned by the need to obtain reliable and accurate data. However, in many cases responding rapidly is equally critical. Location The data were obtained from the Hebridean Mink Project, which was set up with the objective of removing mink from North Uist, Benbecula and South Uist. Methods Here, we introduce an extension of the Dirichlet process mixture (DPM) model of geographic profiling that can be used to estimate source locations of invasions directly from spatial point pattern data without the need to specify dispersal parameters. We use this model to analyse a biological invasion of American mink (Neovison vison) in the Hebrides. Results Our results suggest that sightings data – which are relatively easy and quick to acquire – can be used to capture much of the information about sources of invasive species that is obtained from the harder to acquire and more intensive trap data. Main conclusion These results have important implications for the development of conservation plans and, in this case, in the early stages of biological invasions, when interventions are most likely to be successful.

American alligator (

This article examines the use of rhythmic music in support of people managing co-occuring drug abuse and mental health conditions, and is based on the authors 15 years’ experience as a group counsellor working in this field. Expressive therapies are gaining increasing traction as respected intervention techniques for this client group, as the limits of ‘talk-based’ approaches are exposed. This is particularly true for engaging people in treatment who find discussions confronting or who are uncomfortable with language, including many individuals from minority cultures. Rhythmic music, using hand drums and percussion, is one of the simplest forms of music to introduce into a therapeutic setting and is particularly suited to group therapy. Recent neurological research has showcased the positive impact of rhythmic music for people who have experienced trauma, improving emotional regulation and reducing stress and anxiety associated with relapse. Additionally, experiential therapies such as drumming offer an important balance in residential treatment settings where people may be attending several therapy sessions per day; the result of which can be mental exhaustion. Physical therapies such as drumming can help re-energise clients in these situations, as well as those on sedative medications. Many services resist the introduction of music into their treatment programs due to a perceived lack of expertise or lack of confidence. This article argues that music is too important as a therapeutic healing tool to be left solely to the musical expert, and that many musical exercises, particularly those with a psycho-educational focus that utilise simple rhythmic hand drumming, can be utilised by therapists, with very little musical training, in a fun, empowering and effective way.

American alligator (Alligator mississippiensis) habitats are prone to saltwater intrusion following major storms, hurricanes or droughts. Anthropogenic impacts affecting hydrology of freshwater systems may exacerbate saltwater intrusion into freshwater habitats. The endocrine system of alligators is susceptible to changes in the environment but it is currently not known how the crocodilian physiological system responds to environmental stressors such as salinity. Juvenile alligators were exposed to 12‰ saltwater for 5 weeks to determine the effects of chronic exposure to saline environments. Following 5 weeks, plasma levels of hormones [e.g. progesterone, testosterone, estradiol, corticosterone, aldosterone (ALDO), angiotensin II (ANG II)] were quantified using liquid chromatography and tandem mass spectrometry. Compared with freshwater-kept subjects, saltwater-exposed alligators had significantly elevated plasma levels of corticosterone, 11-deoxycortisol, 17α-hydroxyprogesterone, testosterone, 17β-estradiol, estrone and estriol whereas pregnenolone and ANG II were significantly depressed and ALDO levels were unchanged (slightly depressed). On the one hand, saltwater exposure did not affect gene expression of renal mineralocorticoid and glucorticoid and angiotensin type 1 (AT-1) receptors or morphology of lingual glands. On the other hand, saltwater exposure significantly reduced plasma glucose concentrations whereas parameters diagnostic of perturbed liver function (aspartate aminotransferase and alanine aminotransferase) and kidney function (creatinine and creatine kinase) were significantly elevated. Except for plasma potassium levels (K+), plasma ions Na+ and Cl− were significantly elevated in saltwater alligators. Overall, this study demonstrated significant endocrine and physiological effects in juvenile alligators chronically exposed to a saline environment. Results provide novel insights into the effects of a natural environmental stressor (salinity) on the renin–angiotensin–aldosterone system and steroidogenesis of alligators.

We thank Operation Wallacea for supporting S.C.F. in thisproject and for providing logistical support for the fieldwork,and Aidan Kelsey for invaluable assistance in the field. Wethank the Indonesian Institute of Sciences (LIPI) andKementerian Riset dan Teknologi Republik Indonesia(RISTEK) for providing permission to undertake the work(RISTEK permit no. 211/SIP/FRP/SM/VI/2013, and BalaiKonservasi Sumber Daya Alam (BKSDA) for theirassistance.

The need for materials for high energy storage has led to very significant research in supercapacitor systems. These can exhibit electrical double layer phenomena and capacitances up to hundreds of F/g. Here, we demonstrate a new supercapacitor fabrication methodology based around the microphase separation of PS-b-PMMA which has been used to prepare copper nanoelectrodes of dimension -13 nm. These structures provide excellent capacitive performance with a maximum specific capacitance of -836 F/g for a current density of 8.06 A/g at a discharge current as high as 75 mA. The excellent performance is due to a high surface area: volume ratio. We suggest that this highly novel, easily fabricated structure might have a number of important applications.

American alligators (Alligator mississippiensis) mainly inhabit freshwater habitats but can be exposed to a wide range of salinities during storm surges, droughts or from alterations in freshwater flows. Although some salinization events last weeks, others only last a few days. This study assessed changes in the endocrine function of the renin-angiotensin-aldosterone system (RAAS) and steroid hormone production (steroidogenesis) in juvenile alligators exposed to brackish water (12‰) for 7 days. We quantified plasma levels of angiotensin II and the corticosteroids (aldosterone, corticosterone and 11-deoxycortisol). Various progestogens, androgens, and estrogens were further assessed. The protein expression for the RAAS enzymes, renin and angiotensin converting enzyme (ACE), was quantified immunohistochemically in kidney and lung tissue, respectively, and histology was performed on kidney, lung and gonad tissues. Finally, blood biochemistry parameters such as electrolyte levels and diagnostic indicators for dehydration, renal, and hepatic function were measured. Corticosterone, 11-deoxycortisol, Na+, Cl−, total protein, albumin, uric acid, and cholesterol levels were all significantly elevated in alligators exposed to brackish water compared with alligators in freshwater. The levels of 17β-estradiol and estrone were significantly lowered while histology showed alterations in gonad tissue in the brackish water exposed group. In contrast, while there were no effects of exposure on aldosterone levels, angiotensin II was significantly reduced in brackish water exposed alligators. These results correlated with significantly decreased expressions for both renin and ACE in kidney and lung tissue. Overall, this study showed that short-term exposure of alligators to 12‰ brackish water has significant endocrine effects on juvenile alligators.

Bacterial DNA gyrase is an essential type II topoisomerase that enables cells to overcome topological barriers encountered during replication, transcription, recombination, and repair. This enzyme is ubiquitous in bacteria and represents an important clinical target for antibacterial therapy. In this paper we report the characterization of three exciting new gyramide analogs—from a library of 183 derivatives—that are potent inhibitors of DNA gyrase and are active against clinical strains of gram-negative bacteria (Escherichia coli, Shigella flexneri, and Salmonella enterica; 3 of 10 wild-type strains tested) and gram-positive bacteria (Bacillus spp., Enterococcus spp., Staphylococcus spp., and Streptococcus spp.; all 9 of the wild-type strains tested). E. coli strains resistant to the DNA gyrase inhibitors ciprofloxacin and novobiocin display very little cross-resistance to these new gyramides. In vitro studies demonstrate that the new analogs are potent inhibitors of the DNA supercoiling activity of DNA gyrase (IC50s of 47–170 nM) but do not alter the enzyme’s ATPase activity. Although mutations that confer bacterial cells resistant to these new gyramides map to the genes encoding the subunits of the DNA gyrase (gyrA and gyrB genes), overexpression of GyrA, GyrB, or GyrA and GyrB together does not suppress the inhibitory effect of the gyramides. These observations support the hypothesis that the gyramides inhibit DNA gyrase using a mechanism that is unique from other known inhibitors.

Underwater noise from human activities appears to be rising, with ramifications for acoustically sensitive marine organisms and the functioning of marine ecosystems. Policymakers are beginning to address the risk of ecological impact, but are constrained by a lack of data on current and historic noise levels. Here, we present the first nationally coordinated effort to quantify underwater noise levels, in support of UK policy objectives under the EU Marine Strategy Framework Directive (MSFD). Field measurements were made during 2013–2014 at twelve sites around the UK. Median noise levels ranged from 81.5–95.5 dB re 1 μPa for one-third octave bands from 63–500 Hz. Noise exposure varied considerably, with little anthropogenic influence at the Celtic Sea site, to several North Sea sites with persistent vessel noise. Comparison of acoustic metrics found that the RMS level (conventionally used to represent the mean) was highly skewed by outliers, exceeding the 97th percentile at some frequencies. We conclude that environmental indicators of anthropogenic noise should instead use percentiles, to ensure statistical robustness. Power analysis indicated that at least three decades of continuous monitoring would be required to detect trends of similar magnitude to historic rises in noise levels observed in the Northeast Pacific.

Antibiotic adjuvant therapy represents an exciting opportunity to enhance the activity of clinical antibiotics by co-dosing with a secondary small molecule. Successful adjuvants decrease the concentration of antibiotics used to defeat bacteria, increase activity (in some cases introducing activity against organisms that are drug resistant), and reduce the frequency at which drug-resistant bacteria emerge. We report that 5-alkyloxytryptamines are a new class of broad-spectrum antibacterial agents with exciting activity as antibiotic adjuvants. We synthesized 5-alkyloxytryptamine analogs and found that an alkyl chain length of 6-12 carbons and a primary ammonium group are necessary for the antibacterial activity of the compounds, and an alkyl chain length of 6-10 carbons increased the membrane permeability of Gram-positive and Gram-negative bacteria. Although several of the most potent analogs also have activity against the membranes of human embryonic kidney cells, we demonstrate that below the minimum inhibitory concentration (MIC)-where mammalian cell toxicity is low-these compounds may be successfully used as adjuvants for chloramphenicol, tetracycline, ciprofloxacin, and rifampicin against clinical strains of Salmonella typhimurium, Acinetobacter baumannii and Staphylococcus aureus, reducing MIC values by as much as several logs.

High amplitude anthropogenic noise is associated with adverse impacts among a variety of organisms but detailed species-specific knowledge is lacking in relation to effects upon crustaceans. Brown crab (Cancer pagurus), European lobster (Homarus gammarus) and Norway lobster (Nephrops norvegicus) together represent the most valuable commercial fishery in the UK (Defra, 2014). Critical evaluation of literature reveals physiological sensitivity to underwater noise among N. norvegicus and closely related crustacean species, including juvenile stages. Current evidence supports physiological sensitivity to local, particle motion effects of sound production in particular. Derivation of correlative relationships between the introduction of high amplitude impulsive noise and crustacean distribution/abundance is hindered by the coarse resolution of available data at the present time. Future priorities for research are identified and argument for enhanced monitoring under current legislative frameworks outlined.

Block copolymer lithography based on block copolymer (BCP) self-assembly can be used to develop soft mask nanoscale templates for subsequent pattern transfer to generate substrate features. Self-assembly of lamellar polystyrene- b -polymethylmethacrylate BCP of varying molecular weights to generate silicon nanoscale features is reported here. It has also been demonstrated that the feature size can be controlled by a plasma over-etch process and discussed.

We present a transmission electron microscopy (TEM) investigation of a coupled cobalt and silver nanoparticle system. A plan view in situ lift-out method for preparing samples for TEM using the focused ion beam (FIB) microscope was used. This technique is used to prepare high quality TEM samples with site specificity in a short time and with a high success rate. We demonstrate the ability of the plan view sample preparation technique to provide information about an ordered system of nanoparticles which could not be observed using standard FIB cross sectioning of the sample. High resolution TEM and energy dispersive X-ray spectroscopy mapping of both cross sectional and plan view samples are presented, clearly showing the significant benefit of plan view TEM analysis for certain samples.

Room-temperature ultraviolet lasing in [0001] oriented zinc oxide nanorods grown on silicon and fused silica substrates by a simple vapor transport and condensation process. These wide band-gap semiconductor nanorods form natural laser cavities with diameters varying from 150 to 350 nm and lengths up to 10 µm. Under optical excitation, surface-emitting lasing action was observed at 385 nm. The dielectric core-shell Al2O3@ZnO nanorods exhibit enhanced axial Fabry-Pérot resonating characteristics with (0001) crystal faces as mirror facets improved by a metallic reflector at one end. This metallic coating and dielectric oxide shell greatly increase near-band edge emission while reducing excitation power thresholds due to lower losses and increased optical density from improved refractive index mediated waveguiding during optical pumping.

Actinic cheilitis is a potentially premalignant condition involving predominantly the vermilion of the lower lip. The aim of the current paper was to review the clinical presentation of actinic cheilitis and demonstrate the development of management plans using a series of cases. These are designed to provide immediate treatment where required but also to address the medium and long-term requirements of the patient. The authors suggest that the clinical examination of lips and the assessment of actinic cheilitis and other lip pathology become a regular part of the routine soft tissue examination undertaken as a part of the periodic examination of dental patients. Early recognition of actinic cheilitis can allow the development of strategies for individual patients that prevent progression. These are based on past sun exposure, future lifestyle changes and the daily use of emollient sunscreens, broad-brimmed hats and avoidance of sun exposure during the middle of the day. This is a service that is not undertaken as a matter of routine in general medical practice as patients are not seen with the regularity of dental patients and generally not under the ideal examination conditions available in the dental surgery.

Background: Transplantation therapy for human diabetes is limited by a shortage of donor organs, and transplant function diminished over time by cell death and limited potential for expansion of beta cells in pancreas or islets. Outcomes are complicated by immunosuppression. A way to overcome supply and expansion problems is to xenotransplant embryonic tissue. Previously, we have shown that beta cells originating from embryonic day (E) 28 (E28) pig pancreatic primordia transplanted into the mesentery of streptozotocin (STZ)-diabetic (type 1) Lewis rats or Zucker Diabetic Fatty (ZDF) diabetic (type 2) rats engraft and normalize glucose tolerance without the need for host immune-suppression. Methods: In this study, we transplant E28 pig pancreatic primordia in the mesentery of STZ-diabetic rhesus macaques. Results: Long-term engraftment of pig beta cells within liver, pancreas and mesenteric lymph nodes post-transplantation of E28 pig pancreatic primordia into STZ-diabetic rhesus macaques is demonstrated by electron microscopy, positive immune-histochemistry for insulin, and positive RT-PCR and in situ hybridization for porcine proinsulin mRNA. Insulin requirements were reduced in one macaque followed over 22 months post-transplantation and porcine insulin detected in plasma using sequential affinity chromatography, HPLC and mass spectrometry. Of potential importance for application of this transplantation technology to treatment of diabetes in humans and confirmatory of our previous findings in Lewis and ZDF rats, no host immunosuppression is required. Conclusions: Under selected circumstances, pancreatic primordia elicit a muted immune response relative to more differentiated tissue, such that engraftment occurs in non-immunosuppressed hosts. Our findings that pig pancreatic primordia engraft long-term in non-immunosuppressed STZ-diabetic rhesus macaques establishes the potential for their use in human diabetics.

Breast cancer is a malignant proliferation of epithelial cells lining the ducts or lobules of the breast. Excluding skin cancer, breast cancer is the most common cancer in women. Only lung cancer accounts for more cancer deaths in women. Breast cancer may exist for a long period either as an invasive or noninvasive disease, but not as a nonmetastatic disease. Consequently, timely diagnosis and appropriate management are lifesaving. Approximately 10% of human breast cancers are linked to germline mutations, such BRCA1 and BRCA2. Correct staging of breast cancer patients is critical. It permits an accurate diagnosis, as well as in many cases, therapeutic decisions based largely on the TNM classification. Staging provides the most important prognostic variable. Second opinions of the staging of breast cancer by pathologic examination of the tissue is recommended. There are some variables in which the association with disease-free survival and overall survival seem clear and include estrogen and progesterone receptor cells, S-phase analysis using flow cytometry, histologic classification, molecular changes in the tumor as well as neovasculature semi-quantitative scoring systems. There are four objectives to risk-reducing mastectomy. First, risk-reducing mastectomy should reduce the incidence of breast cancer in high-risk women, for example, BRCA1 or BRCA2 carriers. It should reduce mortality from breast cancer in high-risk women. Moreover, it should have psychological benefits in relieving anxiety about developing breast cancer. Finally, there must be a balance in the reduction in risk against cosmetic outcome, with subsequent quality of life issues. Women should be offered risk reduction mastectomy only on the basis of a strict selection and management plan, like that used in Manchester protocol. This protocol involves a minimum of two sessions with a geneticist/oncologist, a session with a psychiatrist and two sessions with a plastic and reconstructive surgeon with the support of a breast care nurse. The surgical technique should aim at removing substantially all at-risk breast tissue. However, there is an obvious balance between reduction of cancer risk and cosmetic outcome. The surgical technique involves several operations to include the risk-reducing mastectomy as well as breast reconstructive procedures. Skin-sparing mastectomy represents a new surgical approach that allows a mastectomy, whereas preserving the natural skin envelope of the breast. Breast reconstruction will involve several operations, especially if the nipple areola complex is resected and is subsequently reconstructed. The contraindications to risk-reducing mastectomy include the following. The status of the family history or Munchausen's syndrome has not been confirmed. The risk-reducing mastectomy is not the women's own choice. The patient has a current psychiatric disorder including clinical depression, cancer phobia or body dysmorphic syndrome. If the co-morbidity outweighs the clinical benefits, surgery should not be undertaken. Finally, the patient must not have unrealistic expectations of the benefits of surgery. She must understand the subsequent risk-reducing mastectomy may significantly reduce, but not eliminate the risk of subsequent breast cancer.

Discovery and functional evaluation of biologically significant regulatory single nucleotide polymorphisms (SNP) in carcinogen metabolism genes is a difficult challenge because the phenotypic consequences may be both transient and subtle. We have used a gene expression screening approach to identify a functional regulatory SNP in glutathione S-transferase M3 (GSTM3). Anttila et al. proposed that variation in GSTM3 expression was affected by exposure to cigarette smoke and inheritance of the GSTM1-null genotype. To investigate the mechanism of GSTM3 expression was affected by exposure to cigarette smoke and inheritance of the GSTM1-null genotype. To investigate the mechanism of GSTM3 expression variation, we measured GSTM3 expression in lymphoblast cells from a human Centre d'Etude du Polymorphisme Humain family and observed a low expression phenotype. Promoter sequencing revealed two novel GSTM3 promoter SNPs: A/C and A/G SNPs, 63 and 783 bp upstream of the codon 1 start site, respectively. In this pedigree, the two children homozygous for the −63C/C genotype had 8-fold lower GSTM3 expression relative to the two children with the −63A/A genotype, with no association between A−783G SNP and GSTM3 expression. Further evaluation using genotyped glioma cell lines and with luciferase reporter constructs showed that the −63C allele was associated with lower GSTM3 expression (P < 0.0001 and P < 0.003). RNA pol II chromatin immunoprecipitation was combined with quantitative probed-based allelic discrimination genotyping to provide direct evidence of a 9-fold reduced RNA pol II binding capacity for the −63C allele. These results show that the GSTM3 −63C allele strongly affects gene expression in human cell lines and suggests that individuals who carry the low expression allele may be deficient in glutathione transferase catalyzed biological functions.

Background Severe, refractory hypoxemia complicating uncorrected cyanotic congenital heart disease is a potentially lethal condition, even when urgent surgical intervention is undertaken. When a viral pneumonia initiates hypoxemia, the likelihood of a satisfactory outcome is further reduced. We examined our policy of venovenous extracorporeal membrane oxygenation support through the hypoxic event and performing delayed surgery, if required, to separate from extracorporeal membrane oxygenation. Methods A single institution, retrospective review of an Institutional Review Board approved database was undertaken. Over a 6-year period, 18 instances were identified for 17 patients who became acutely hypoxemic from either inadequate pulmonary blood flow (8 instances) or a viral pneumonia (10 instances) complicating their cyanotic heart disease. Demographics, duration of venovenous extracorporeal membrane oxygenation and outcomes are reported. Results The length of venovenous extracorporeal membrane oxygenation ranged from 13.5 to 362.5 hours (mean 130 ± 121 hours). During 10 supports, operations were performed to facilitate weaning from support. In 7 patients, extracorporeal support was weaned during this surgery. Follow-up was obtained in all patients over a period ranging from 4 months to 7 years (mean 39.0 ± 23.0 months). There were two late deaths due to sepsis 1.4 and 2.5 months after extracorporeal support. Conclusions Venovenous extracorporeal membrane oxygenation allows time for the recovery of acute hypoxic insult and resolution of some viral pneumonia processes. Palliative surgical procedures may be safely undertaken during extracorporeal support. Viral pneumonia is a risk for prolonged support. Venovenous extracorporeal membrane oxygenation is useful in these high-risk patients.